PROJECT SUMMARY The alarming spread of tuberculosis (TB), and co-epidemic of HIV-associated TB, are global health concerns. Despite the availability of effective anti-mycobacterial and anti-viral therapy, growing drug-resistance, and increased morbidity and mortality associated with HIV co-infection, have prompted an exigent need to develop innovative therapies. A key feature of host immune response to Mycobacterium tuberculosis (M.tb) is the formation of aggregates of immune cells called granulomas, predominantly in the lungs, which provide the microenvironment in which infections are contained, but which also allow for pathogen persistence and ultimate reactivation of dormant infection, as seen in HIV. We hypothesize that by dampening host immunosuppressive responses mediated by regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSC), and by eliminating immune cells that engulf and harbor M.tb, the host immune response could be tipped towards a predominantly anti-mycobacterial one leading ultimately to eradication of infection. In this study, we propose to test the efficacy of new and improved preparations of DAB389mIL-2 (Ontak) and DAB389mIL-4, specific diphtheria toxin-based cytokine receptor targeted fusion proteins generated in our laboratory, in the selective elimination of cells, such as Tregs and MDSC, expressing IL2-R and IL-4R respectively. We will evaluate them as host directed therapeutics in mouse models of TB and of M.tb/HIV co-infection in order to develop them further for primate model studies and human clinical trials. .